Hepatokines are hepatocyte-derived autocrine or paracrine growth and survival factors. Preliminary data described below demonstrates the identification of a novel hepatokine (HK-1) originally isolated from fetal hepatocytes and patented by this laboratory. The overall goal of the present project is to produce sufficient quantities of recombinant HK-1 to evaluate its capacity to enhance pancreatic islet cell survival and transplantation. HK-1 is mitogenic for hepatocytes and hepatocyte cell lines and promotes the survival of fetal pancreas and hepatocytes. Highly purified HK-1 protects mice from acute CCI4-induced liver cell injury and augments the success of fetal pancreas transplantation. In phase I we will express the cDNA for HK-1 and purify sufficient quantities of protein for biological studies, evaluate he activity of HK-1 using in vitro assays of apoptosis, growth and differentiation and study the in vivo activity of HK-1 in an animal model of diabetes mellitus. In Phase II we will carry out more in-depth studies of HK-1 in conjunction with allogeneic pancreas transplantation. Depending upon the success of these studies, HK-1 will be produced under GMP conditions, subjected to formal toxicology and preclinical studies in preparation for submission of an IND.